2. Management of the treatment-naïve patient with HCV infection Paul Desmond Greg Dore

3. Learning objectives 1.Patient factors involved in treatment decisions 2.Viral factors in treatment decisions 3.Logistics in using DAAs 4.Management of side-effects of DAAs 5.Role of IL-28B testing 6.Role of ribavirin monitoring

4. Mrs LF 57-year-old housewife Presents to GP with tiredness ALT 65 U/L HCV antibody positive Otherwise well On examination NAD

5. Mrs LF Risk factors for HCV Husband had liver transplant in 2007 for decompensated HCV/alcohol-related cirrhosis NO IV drug use or blood transfusion

6. Question What other investigations would you order?

7. Mrs LF - ALT 62 U/L - Albumin 40 g/L - Platelets 247 x 10 9 /L - HCV PCR Positive - HCV VL 4,730,000 IU/mL - Genotype1a

8. Questions Genotype 1a vs 1b? Viral load? Influence on response to treatment?

9. Telaprevir in G1 patients: Impact of host and viral factors Marcellin P, et al. Poster 451; Dusheiko GM, et al. Poster 415. Posters presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 100 0 50 Genotype 79 71 Race 75 62 Fibrosis F0-2 F3-F4 62 78 Patients Achieving SVR (%) Results represent telaprevir (T12PR) populations Treatment-naïve GT1 patients 75 25 Non-BlackBlack 1b 1a Viral load LVL HVL 78 74

10. GTG (V36) HCV Genotype 1b has a higher genetic barrier than Genotype 1a Subtype 1aSubtype 1b GTG (V36) ATG (V36M) GTCATC (V36) ATCATGATG (V36) (V36M) www.hivforum.org 1 step 2 steps GTC (V36)

11. Question Any further investigations?

12. Mrs LF FibroscanLiver stiffness 7.9 KPa IL28BC/T

13. Question What should we do now? - Genotype 1a - High viral load - F2-F3 fibrosis - IL28B C/T

14. Ge*, Fellay*, Thompson* et al. Nature 2009

15. Multivariate analysis of baseline predictors of SVR (genotype 1 HCV) ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level (n=1604), plus 67 patients from another trial (race based on self-report, similar to clinical practice setting) Thompson AJ, et al. Gastroenterology. 2010;139:120-129. Predictor Adjusted Odds Ratio (95% CI)P Value rs12979860 CC5.2 (4.1-6.7)< 0.0001 HCV RNA level ≤ 600,000 IU/mL3.1 (2.3-4.1)< 0.0001 White vs black2.8 (2.0-4.0)< 0.0001 Hispanic vs black2.1 (1.3-3.6)0.0041 METAVIR F0-F22.7 (1.8-4.0)< 0.0001 Fasting blood sugar < 5.6 mmol/L1.7 (1.3-2.2)< 0.0001

16. 0 20 40 60 80 100 Patients (%) 69% SVR 75% 44% TVR 12 + PR PR 48 TVR 8 + PR 63% 66% 38% SVR BOC RGT PR 48 BOC 44 HCV-1 Rx-naïve (ADVANCE/SPRINT-2) TelaprevirBoceprevir

17. Mrs LF Entered a clinical trial: Telaprevir BD vs Telaprevir TID

18. Transfusion RBV dose 1000 mg 600 mg End of treatment Mrs LF – Haemoglobin during treatment

19. Anaemia management on telaprevir Ribavirin dose reduction Transfusion EPO

20. Mrs LF – Telaprevir side effect (rash)

21. SIDE EFFECTT12T8PR (T)BOC 44BOC RGTPR (B) Fatigue57%58%57% 53%60% Pruritus50%45%36% Headache41%43%39%46% 42% Nausea43%40%31%43%48%42% Rash37%35%24% Anaemia37%39%19%49% 29% EPO Use43% 24% Insomnia32% 31%33%32%33% Diarrhoea28%32%22% Flu Sx28%29%28%33%36%28% Pyrexia26%30%24%33% 32% Anorectal Sx13%8%4% Dysgeusia43%37%18% TVR & BOC: Adverse events

22. Treatment of TVR rash RASH Mild Moderate Severe SCAR Emollients, topical corticosteroids, antihistamines, limit sun exposure, loose fitting clothes ? Derm R/V If progresses, cease TVR If no improvement in 7 days, stop RBV Permanently cease TVR Monitor for progression/systemic symptoms If no improvement in 7 days, stop RBV+/- peg-IFN Permanent and immediate cessation of TVR Derm R/V

23. SCAR (Severe Cutaneous Adverse Reaction) Cacoub P et al. J Hepatol 2012;56:455-463 SCAR encompasses several conditions Acute generalised exanthematous pustulosis (AGEP) and Erythema Multiforme Major (EMM) Drug rash/reaction with eosinophilia and systemic symptoms (DRESS) Toxic epidermal necrolysis (TEN) and Stevens- Johnson Syndrome (SJS) 11 cases suggestive of DRESS 3 cases suggestive of SJS (1 case considered not related to telaprevir, onset 11 weeks after telaprevir discontinuation)

25. Mrs LF – Results on treatment WeekHbNeutrophilsPlateletsALTPCR 01354.3330450 41191.211917Neg 8841.239918Neg 1287113727Neg 16911.613914Neg 24920.8711315Neg 48 Neg

26. Ms CB – Presentation (July 2008) 52-year-old, retired De facto male partner (HCV +ve) 2 children (18, 26 years: HCV –ve) Lives in Far South Coast NSW Smoker: 20 cigarettes/day Alcohol: 40 – 60 grams/day Medications: Nil

27. Ms CB – Presentation (July 2008) HCV diagnosis: 1995 Risk factors: IDU 1979 – late 2007 Symptoms: mild lethargy Past medical Hx: chronic anxiety Clinical exam: NAD

28. Ms CB – Baseline investigations (July 2008) LFTs: Alb 44, Bil 8, AST 49, ALT 44, GGT 127 FBC: Hb 153, Neut 3.3, Plats 275 Genotype: 1 (no subtype) HCV RNA: >700,000 IU/ml Fibroscan: 8.1 (November 2008) Management Plan: Alcohol reduction; defer HCV treatment

29. Ms CB – Follow-up January 2010: Continued alcohol intake 40-60 g/day No repeat Fibroscan performed October 2011: Continued alcohol intake 40-60 grams/day Fibroscan: 12.0 kPa Genotype : 1a, HCV viral load 2 million IU/mL LFTS: Alb 44, Bil 7, AST 67, ALT 82, GGT 134 FBC: Hb 148, Neut 2.1, Plats 229 AFP: 26.1

30. Ms CB – Follow-up February 2012: No further alcohol intake Fibroscan: 13.1 kPa Preparation for HCV treatment Abdominal U/S: NAD No features of cirrhosis/portal H/T No IL28B testing available

31. Issue 1: Would result of IL28B testing (if available) have influenced choice of treatment regimen?

32. SPRINT-2: IL28B and DAA response Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 SVR (%) 50/64 n/N= CCTT 44/55 CT 63/7733/116 82/11567/10310/37 26/44 23/42

33. HCV treatment: peg-IFN/RBV(BOC) April 2012 (baseline): Peg-IFN-alfa-2a (180 mcg/week) + RBV 1000 mg/day LFTs: Alb 41, Bil 7, AST 63, ALT 83, GGT 87 HCV VL:2.08 million (6.3 log)

34. HCV treatment: peg-IFN/RBV(BOC) May 2012 (week 4): Peg-IFN-alfa-2a (180 mcg/week) + RBV 1000 mg/day AEs: Lethargy, dyspnoea on exertion, insomnia LFTs: Alb 40, Bil 12, AST 43 (63), ALT 44 (83), GGT 124 (87) FBC: Hb 96 (142), Neut 1.4 (2.3), Plats 218 (213) HCV VL:203,400 (5.3) (2,086,900 (6.3) ) RBV conc:2.96

35. Issue 2: Given the decline in HCV VL over weeks 0 – 4, what is the prospect of SVR? Would the decline in VL influence subsequent treatment?

36. SPRINT-2: SVR by lead-in viral decline >1 log decline <1 log decline HCV RNA week 0-4 (Non-black) Poordad F, et al. NEJM 2011;364:1195-1206

37. Issue 3: Role of EPO vs RBV dose reduction? Role for monitoring of serum RBV concentration?

38. 48 PR (n=363)BOC RGT (n=368)BOC/PR48 (n=366) Median treatment duration, days203197335 DeathsN= 4N=1 Serious AEs9%11%12% Discontinued due to AEs16%12%16% Dose modifications due to AEs26%40%35% Haematologic parameters Neutrophil count (< 750 to 500/mm 3 /< 500/mm 3 )14%/4%24%/6%25%/8% Haemoglobin (< 10 to 8.5 g/dl/<8.5 g/dL)26%/4%45%/5%41%/9% Discontinuation due to anaemia1%2% Dose reductions due to anaemia13%20%21% Erythropoietin use24%43% Mean (median) days of use121 (109)94 (85)156 (149) Poordad F, et al. NEJM 2011;364:1195-1206 SPRINT-2: Adverse events

39. After completion of 4 week peg-IFN/RBV lead In, all patients initiated boceprevir Haemoglobin ≤10 g/dL RBV DR (200-400 mg) EPO (40,000 IU/wk SC) R Haemoglobin ≤8.5 g/dL: Secondary Strategy (EPO, RBV DR, transfusion) R = randomisation DR, dose reduction; EPO, erythropoietin; peg-IFN, peg-interferon; RBV, ribavirin; SC, subcutaneously. EPO vs ribavirin dose reduction in peg-IFN/RBV/BOC HCV treatment naïve, genotype 1 (n=687) Poordad F, et al. EASL 2012

40. Enrolled n=687 SVR=62.7% (431/687) Met protocol-defined anaemia criteria n=500 SVR=71.2% (356/500) RBV DR and continued peg-IFN/RBV+BOC n=249 SVR=71.5% (178/249) EPO added and continued peg-IFN/RBV+BOC n=251 SVR=70.9% (178/251) Did not meet protocol-defined anaemia criteria (pending randomisation arm) n=187 SVR=40.1% (75/187) Did not meet anaemia criteria; completed peg-IFN/RBV+BOC treatment n=64 SVR=89.1% (57/64) Did not meet anaemia criteria; did not complete treatment n=92 SVR=19.6% (18/92) Discontinued during lead-in n=31 SVR=0% (0/31) Poordad F, et al. EASL 2012 73%27%

41. CHARIOT study: RBV conc and SVR (n=210) Ali R, et al. EASL 2011

42. HCV treatment: peg-IFN/RBV/BOC May 2012 (week 5): RBV reduced from 1000 mg to 600 mg Commenced on BOC (800 mg tds) June 2012 (week 9, (BOC week 4)): Peg-IFN-alfa-2a (180 mcg/week) + RBV (600 mg/day) + BOC (800 mg tds) LFTs: AST 26 (63, 43), ALT 21 (83, 44), GGT 54 (87, 124) FBC: Hb 97 (142, 96), Neut 0.9 (2.3, 1.4), Plats 146 (213, 218) HCV RNA:Undetectable (<15 IU/ml)

43. Issue 4: Duration of treatment?

44. SPRINT-2: SVR by treatment arm Non-black (n=938) Black (n=159) Poordad F, et al. NEJM 2011;364:1195-1206

45. Mr MD 47-year-old owner/operator of a trucking business HCV diagnosed in 2010 (IV DU 25 years ago) Moderate alcohol intake until 2010 Working fulltime, few symptoms Genotype 1a, viral load 2,230,000 IU/mL ALT 242 U/L Platelets 56, Albumin 24 g/L Varices banded 2011

46. Genotype 1a Viral load 2,230,000 IU/mL IL28B C/T Fibroscan 42.2 KPa Mr MD

47. Question Mr MD: Severe cirrhosis Portal hypertension Very active inflammation What can we offer him?